Chewing Gum As Drug Delivery System

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Nazneen Z. Ratlam

It is well known fact that the right drug delivery system is
critical to the success of a pharmaceutical product.

A novel drug delivery system creates additional patient benefits that will
add new competitive advantages for a drug and, thus, conserve or increase revenue.Chewing
gum as drug delivery system holds tremendous potential not only in smoking cessation
and oral health care arenas but also in other indications.

Introduction:

Oral route is the most preferred route amongst the patient and clinicians
due to various advantages it offers.

However, preoral administration of drugs has disadvantages such as hepatic
first pass metabolism and enzymatic degradation within the GI tract, that prohibit
oral administration of certain classes of drugs. Transmucosal routes of drug
delivery offer distinct advantages over preoral administration for systemic
drug delivery that are bypass of first pass effect, avoidance of presystemic
elimination within the GI tract and a better enzymatic flora for drug absorption.

People of all cultures chew gum, and a variety of gums and gum-like substances
have been enjoyed for thousands of years.{josquote} Medicated chewing gum is
nothing but gum base containing an active substance either in its core or coating.
{/josquote}The introduction and subsequent success of nicotine chewing gum in
the 1980’s paved the way for a more general acceptance of chewing gum as a drug
delivery system. Improved technology and extended know-how, together with the
inclusion of medical chewing gum in the European
pharmacopoeia
in 1998, have further contributed to the acceptance of this
method of drug delivery.

Why use chewing gum as drug delivery system?

Chewing gum provides new competitive advantages over conventional drug delivery
system:

  • Fast onset of action and high bioavailability
  • Pleasant taste
  • Higher compliance (easy and discreet administration without water)
  • Ready for use
  • High acceptance by children

Fewer side effects:

Low dosage gives high efficacy as hepatic first pass metabolism is avoided. The controlled release rate also reduces the risk of side effects, as high plasma peak concentrations are avoided.

Systemic effect

Active substances can be absorbed through the buccal mucosa and/or through the GI tract when saliva is swallowed. Once the active substance is present in the blood, systemic affect can be obtained.

Fast onset of action:

Fast onset of systemic effect is seen for active substances absorbed through the buccal mucosa, as the active substances pass by the jugular veins directly to the systemic circulation.

Local effect:

Chewing gum is an obvious drug delivery system for local treatment of diseases in the oral cavity and in the throat, as sustaining the release of active substances may deliberately prolong exposure.

Effect on dry mouth ( xerostomia):

Dry mouth is a side effect of many types of medicament (e.g. antidepressants) and it is also part of the symptomatology of several diseases (e.g. sjogren’s syndrome-an autoimmune disorder characterized by lymphocytic infilteration of the salivary and lacrimal glands). Chewing gum stimulates salivary secretion thereby decreasing dryness in the mouth.

Concept of formulation development:

A piece of chewing gum usually consists of gum core, which may or may not be coated. The core is composed of an insoluble gum base resin, elastomers, emulsifiers, fillers, waxes, antioxidants and softeners, sweetners, flavoring agents, and in case of medical chewing gum, active substances. The water content of chewing gum is very low and no preservative is needed. The gum base determines the basic characterstics of the product, e.g. the texture: is soft or hard to chew? Does it crumble? Does it stick to the teeth? The gum base also determines the release profile of active substances and changing the gum base compostion may therefore change the release profile.

As many active substances are lipophillic, they will adhere to the gum base
and may therefore be released slowly and incompletely. Methods to increase rate
and extent of the release include the addition of buffering agents or solubilizing
agents and coating/encapsulating the active substances. In contrast, hydrophillic
active substances are rapidly released and it may therefore be necessary to
slow down the release rate by means of various methods, like encapsulating the
active substances or by increasing the amount of gum base. The water content
of gum base is very low and the gum binds lipophillic substances very firmly.
In order to obtain the optimal formulation it is possible to decrease the release
rate go highly lipophilic substances and increase the release rate of lipophillic
substances.

Changing the water solubility of the active substances will increase or delay
the release. A similar effect may be obtained by changing the hydrophilic/lipophillic
balance of the chewing gum formulation. {/josquote}The simplest way of achieving this is
to increase or decrease the amount of gum base. An increase in t5he gum base
will make the formulation more lipophillic and thus reduce the release rate
of a given active substance. To obtain a viable formulation, it is far more
effective to change the release properties by adding solubilizers to the formulation.

To succeed in the market, a chewing gum formulation must have a pleasant taste and texture. Most active substances have an unpleasant, bitter, or metallic taste. Since the active substance will be released in the oral cavity and remain there for a longer period of time than is the case with oridinary delivery forms, unique expertise in taste definition, taste masking and taste modification are essential to the success of a medical chewing gum product.

One of the major challenges for the product developer is that any small adjustment
in the amount of active ingredient, flavor, sweetener, or gum base component
may lead to changes in several parameters. Therefore every active ingredient
requires a custom-made gum base.

The gum base determines the basic characteristics of the product like the texture,
its softness, hardness, elasticity, crumbleness, stickiness, mouthfeel etc.
It also determines the release profile of active ingredients and flavors.

Formulation

The main components of medicated chewing gum are:

Active substances- vitamins, oral contraceptives, nicotine,
minerals, analgesics, antacids, muscle relaxants, antihistamines, decongestants,
anesthetics, antitussives, antibiotics, etc.

Flavors- essential oils like citrus, peppermint, spearmint,
anise and wintergreen oil are employed as flavors. Synthetic flavors are also
used.

Sweetners- Sugar free chewing gums contain sweetening agents
like sorbitol, mannitol, aspartane, saccharin etc

Gum base- Natural or synthetic gum base is used. Example of
synthetic gum base includes styrene butadiene rubber, polyethylene and polyvinyl
acetate. Smoked rubber is natural source.

In addition to above ingredients various additives are also used to improve
properties of chewing gum, like plasticizers, elastomers, lipids (soyabil),
emulsifiers (lecithin), softners and fillers, texture agents (talc), coating
and binding agents, film formers, coloring agents etc. Corn syrup keeps the
gum flexible and fresh. Xylitol has been investigated to play a significant
role in dental caries.

Manufacturing process

In general, chewing gum is manufactured by sequentially adding the ingredients to a commercially available mixer known in the art. After the ingredients have been thoroughly mixed, the gum mass is discharged from the mixer and shaped into the desired form such as extruding in to chunks or casting into pellets which are then coated or panned. The ingredients are mixed by first melting the gum base and adding to it the running mixer. The base may be melted in the mixer itself and other additives added at this time. The entire procedure takes from 5-15 min, but longer mixing time may be manufactured depending on the texture and function of gum base.

Oral Mucosa

The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. Epithelium has a mitotically active basal cell layer, advancing through a no. of differentiating intermediated layers to the superficial layers, when cells are shed from the surface of the epithelium. The epithelium cells increases in size and becomes flatter as they travel from the basal layer to the superficial layers.

It is estimated that the permeability of the buccal mucosa is 4-4000 times
greater than that of the skin. In general the permeabilities of the oral mucosa
decreases in order of sublingual greater than buccal and buccal greater than
palatal. The main target mucosa for drug absorption from chewing gum formulation
is sublingual mucosa. However, drug is released into saliva and its subsequent
spreading may cause the drug to be absorbed across other mucosa of oral cavity.

Because of the high permeability and the rich blood supply, the sublingual
route is capable of producing a rapid onset of action making it appropriate
for drugs with short delivery period requirement with infrequent dosing regimen.
Buccal mucosa on the other hand is more suited for sustained delivery applications
as it is less permeable and has immobile mucosa.

The buccal mucosa consists of 20-40 layers of cells with a total thickness
of 450-600mm. The main barrier of the buccal mucosa is situated in the outer
one third of the epithelium. The submucosa is highly vascularized and rapidly
removes any permeated active substances to the systemic circulation thus avoiding
first pass metabolism.

In-vitro testing

The absorption of active substances through the buccal mucosa can be examined by both in vitro and in vivo methods. The most common method utilizes Ussing chamber where excised buccal mucosa (either from human or animal) is placed as a barrier between two chambers. The transport of active substances across the mucosa is measured by withdrawal of samples from each chamber. Porcine oral cavity is recommended, as it is morphologically similar to human oral cavity.

A second method employs a human TR146 cell culture model for investigating permeability effects and toxic effects. TR146 cells are derived from human buccal carcinoma and grown in layers with morphologically resemble human buccal mucosa.

In vitro Apparatus

An apparatus was specially designed and constructed for release testing of
medicated chewing gums. The adjustable instrumental settings such as temperature,
chewing frequency, chewing time, volume of test medium, distance between the
jaws and twisting angle increased the versatility of the apparatus. Selection
of the test medium was also an important parameter. Each sample was kneaded
mechanically in separate test chambers and the drug release was followed by
sampling and HPLC analysis. Different gum formulations were tested and the obtained
results demonstrated satisfactory release curves for a variety of formulations
and active ingredients. The tested gum formulations comprised nicotine, meclizine,
dimenhydrinate and xylitol. The apparatus proved to be suitable in product control
of commercial batches but also a useful tool in the research and development
of medicated gum formulations.

In vivo studies

Buccal absorption of active substances can also be tested by various in-vivo methods. Beckett and Triggs introduced a mouth wash procedure in 1967, in which a buffered solution of the active substances is swirled in the oral cavity for a known period of time. Subsequently the solution is expelled and the oral cavity is rinsed with buffer. The difference between the amount of active substance contained in the original solution and the amount recovered is the amount of active substance absorbed from the oral cavity.

Applications

1.Dental caries- Prevention and cure of oral disease are obvious targets
for chewing gum formulations. It can control the release rate of active substances
providing a prolonged local effect. It also re-elevates plaque pH which lowers
intensity and frequency of dental caries. Fluoride containing gums have been
useful in preventing dental caries in children and in adults with xerostomia.
Chlorhexidine chewing gum can be used to treat gingivitis, periodontitis, oral
and pharyngeal infections. It can also be used for inhibition of plaque growth.
Chlorhexidine chewing gum offers numerous flexibility in its formulation as
it gives less staining of the teeth and is distributed evenly in the oral cavity.
The bitter taste of chlorhexidine can be masked quite well in a chewing gum
formulation.

2.Systemic therapy- chewing gum as a drug delivery system is beneficial
to a number of indications, some of which are discussed below:

a)Pain- Treatment of minor pains, headache, muscular aches can be successfully
accomplished

b)Smoking cessation- Chewing gum formulation containing nicotine, lobeline
and silver acetate have been clinically tested as aids to smoking cessation.
Nicotine is a natural alkaloid occurring in the leaves of tobacco plant. It
is a therapeutic agent intended to help smokers break the psychological habit
of smoking by reducing the nicotine withdrawal symptoms normally experienced
when smoking is stopped. The formulation nicoretteÒ available as mint and classic
with different flavor and dosage, is developed with ion- exchange resin, released
90% of drug after 30 min chewing (Russel et.al 1980). The release rate was controlled
by the rate and vigour of chewing. Thus the patient can control the drug intake
to match his needs. Increasing the pH of the medium in which it is dissolved
can enhance nicotine absorption.

c)Obesity- Active substances like chromium, guaran and caffeine are proved
to be efficient in treating obesity. Chromium is claimed to reduce craving for
food due to an improved blood-glucose balance. Caffeine and guaran stimulate
lipolysis and have a thermogenic effect (increased energy expenditure) and reduce
feeling of hunger.

d)Other indications- xerostomia, Allergy, Motion sickness, Acidity, Cold and
Cough, Diabetes, Anxiety etc are all indications for which chewing gum as drug
delivery system could be beneficial.

Marketed products  

PRODUCT

 

DRUG

 

INDICATION (S)

Nicorette®

Nicotinell®

NiQuitin CQ®

Fluorette®

Vitaflo CHX®

Advanced+®

HEXIT®

Stay Alert®

Travvell®

 

Nicotine

Nicotine

Nicotine

Fluoride

Chlorhexidine

Chlorhexidine

Chlorhexidine

Caffeine

Dimenhydrinate

Smoking cessation

Smoking cessation

Smoking cessation

Prevention of dental caries

Antibacterial

Prevention of caries

Antibacterial

Motion sickness

Limitations of Chewing gum as Drug Delivery System

Chewing gum has several disadvantages as the drug released into saliva disappears rapidly from the oral cavity because of involuntary swallowing. The concentration of drug in the oral cavity always tends to decrease as a result of salivary dilution. Also, Drug release from chewable formulations has shown to be strongly influenced by the way patient chews the formulation. Administration of such dosage form is restricted to short period of time because the presence of the delivery system in the oral cavity causes disturbance in drinking, eating and speaking. Despite these limitations, chewing gum formulation affords extended delivery period compared to solution and fast dissolving tablets.

Future Trends

Chewing gum not only offers clinical benefits but also is an attractive, discrete and efficient drug delivery system. A few decades ago, the only treatment for some disease was surgical procedure but now more and more disease can be treated with Novel Drug Delivery Systems. Generally, it takes time for a new drug delivery system to establish itself in the market and gain acceptance by patients, however chewing gum is believed to manifest its position as a convenient and advantageous drug delivery system as it meets the high quality standards of pharmaceutical industry and can be formulated to obtain different release profiles of active substances.

Conclusion

Chewing gum is an excellent drug delivery system for self-medication, as it is convenient and can be administered discreetly with out water. It offers several advantages compared to chewable tablets, lozenges and other related formulations hence in the coming years it is very likely that chewing gum will become a common drug delivery system.

Bibliography

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About Authors:

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* Corresponding Author: Nazneen Z. Ratlam , MAEER’S Maharashtra
Institute of Pharmacy, Pune-411038, e-mail : nazkulsum@yahoo.com

Jagdale Swati

Ms Swati Jagdale
is working as Assistant Professor in Pharmaceutics at MAEER’S Maharashtra Institute of Pharmacy, Pune-41103

Pharma Student Magazine: 

Comments

Hemangi Purarkar's picture

Hi, Nazneen
nice article and a very good presentation for such drug delivery system because Chewing gum ia used very commonly by large no. of populations if such kind of delivery systems arises then it will be more patient compliance

ROHAN DESHPANDE's picture

can Montelukast sodium be administered my chewing gum delivery system?
ROHAN DESHPANDE JSS college of pharmacy, Mysore-5700 15.